This is a 35 U.S.C. xc2xa7 371 National Stage application of International Application PCT/JP00/05753, filed Aug. 25, 2000, which designates the United States of America and was published under PCT Article 21 (2) in Japanese.
The present invention relates to a method for producing oxo-oxazoline derivatives using a simple and inexpensive method.
Oxo-oxazoline derivatives are critical intermediates for compounds (WO98/08867) which are TRH (thyrotropin releasing hormone) derivatives represented by the following general formula (VIII): 
wherein RA is a hydrogen atom or optionally substituted lower alkyl; Y is an optionally substituted alkyl.
Further, compounds represented by the following general formulas (III-A), (III-B), (IV-A), or (IV-B): 
wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl, and derivatives thereof, are useful as tools for combinatorial chemistry.
Conventionally, as a method for producing oxo-oxazoline derivatives having a lower alkyloxycarbonyl group or a carboxyl group, a method of cyclizing a starting material while retaining its stereochemistry, and a method using cyclization reaction without reference to stereoselectivity are known.
An example of the method of cyclizing a starting material while retaining its stereochemistry is the following: 
(Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonine used as a starting material is allowed to react with phosgene and potassium hydroxide in toluene at 0xc2x0 C. for one hour, thereby obtaining a cyclized product which retains its stereochemisty. Unfortunately, this method encounters a problem in industrialization since the method employs L-allo-threonine which is more expensive than its natural type, and phosgene which is toxic to the human body.
An example of the cyclization method without reference to stereoselectivity is the following: 
(Japanese Laid-Open Publication No. 60-34955). In this reaction, a starting material is allowed to react with potassium carbonate in water at 60xc2x0 C. for 1.5 hours to obtain a cyclized product. It is believed that the stereochemistry of the material is maintained in view of the mechanism of this method. Therefore, it is considered that allo-threonine needs to be used as a starting material in order to obtain a cis-form cyclized product.
Although a resultant cyclized product is an oxo-oxazoline derivative which does not have a lower alkyloxycarbonyl group or a carboxyl group, the following method is known: 
(Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, a starting material is allowed to react in thionyl chloride at 60xc2x0 C. for 24 hours without solvent, thereby obtaining a cyclized product at a yield of 65%. In this method, similar to the method of the present invention, the position of an ethyl group is inverted after the reaction. However, the starting material is not an amino acid derivative, and the relationship between the amino group and the hydroxyl group of the starting material is different from that of a starting material used in the method of the present invention. Moreover, since the reaction is conducted in thionyl chloride, the yield is as low as 65%.
Similar to the method of the present invention, a cyclization reaction with inversion is known: 
(Heterocycl. Commun., 2, 55, 1996). An example in which trifluoroacetic anydride is used in the first step is disclosed. Although in the method of the present invention, the yield of a cyclization reaction is as high as 83%, the yield of the cyclization reaction disclosed in the above-described publication is as low as 40% in both a method using tosyl chloride and a method using trifluoroacetic anydride. Moreover, the method of the present invention is superior in regard to simplicity of reaction.
The objective of the present invention is to provide a method for producing oxo-oxazoline derivatives in a simple, inexpensive and stereoselective manner. The oxo-oxazoline derivatives are useful as intermediates for pharmaceuticals and tools for combinatorial chemistry. Moreover, the oxo-oxazoline derivatives in an open-circular form are also useful as tools for combinatorial chemistry.
The inventors found a method for producing oxo-oxazoline derivatives in a stereoselective manner, which is suitable for large-scale synthesis.
That is, the present invention relates to
I) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of treating a compound represented by a general formula (II-A) or a general formula (II-B) with thionyl chloride as follows: 
wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl; R2 is a lower alkyl, an optionally substituted aralkyl, or an optionally substituted heteroarylalkyl; and R3 is a lower alkyl.
More specifically, the present invention relates to following II) to X).
II) A method for the production according to I), wherein the compound represented by the general formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 5.0 equivalents of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 30xc2x0 C. to ref lux temperature.
III) A method for the production according to I), wherein the compound represented by the general formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 3.0 equivalents of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 60xc2x0 C. to 80xc2x0 C.
IV) A method for the production of a compound represented by a general formula (III-A) or a general formula (III-B), comprising the step of subjecting a compound represented by a general formula (I-A) or a general formula (I-B) obtained by a method according to any of I) to III) to a hydrolysis as follows: 
wherein R1 and R3 are as described above.
V) A method for the production of a compound represented by a general formula (IV-A) or a general formula (IV-B), comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a hydrolysis as follows: 
wherein R1 is as described above.
VI) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of protecting the amino group of a compound represented by a general formula (V-A) or a general formula (V-B) with R2OC(xe2x95x90O)xe2x80x94, wherein R2 is as described above, esterifying the carboxyl group thereof, and treating with thionyl chloride as follows: 
wherein R1 and R3 are as described above.
VII) A method for production of a compound represented by a general formula (VI): 
wherein R1 is as described above, and Y is an optionally substituted alkyl, comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a peptide bond formation.
VIII) A method for the production according to IV), wherein R1 is phenyl, 5-imidazolyl, methyl, isopropyl, ethynyl, or 1-propynyl.
IX) A method for the production according to IV), wherein R2 is a lower alkyl, an aralkyl, or a heteroarylalkyl.
X) A method for the production according to IV), wherein R2 is an aralkyl.
XI) A method for the production according to IV), wherein R1 is methyl and R2 is benzyl.
xe2x80x9cHalogenxe2x80x9d as used herein refers to fluorine, chlorine, bromine, and iodine. Chlorine and bromine are preferable.
The term xe2x80x9clower alkylxe2x80x9d as herein used alone or in combination with other words comprises C1-C6 straight chained or branched alkyl. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and t-butyl, and the like. Methyl and ethyl are preferable.
xe2x80x9cAlkynylxe2x80x9d as used herein comprises C2-C8 straight or branched chain monovalent hydrocarbon group having one or two or more triple bonds. The alkynyl may have a double bond. Examples of the alkynyl include ethynyl, 1-propynyl, 2-propynyl, 6-heptynyl, 7-octynyl, and8-nonyl, and the like. Ethynyl and 1-propynyl are preferable.
The term xe2x80x9carylxe2x80x9d as herein used alone or in combination with other words comprises a monocyclic or condensed ring aromatic hydrocarbon. Examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, anthryl, and the like.
xe2x80x9cAralkylxe2x80x9d as used herein comprises the above-described xe2x80x9clower alkylxe2x80x9d substituted with the above-described xe2x80x9carylxe2x80x9d, where the substitution may be carried out at any possible position. Examples of the aralkyl include benzyl, phenylethyl (e.g., 2-phenylethyl, and the like), phenylpropyl (e.g., 3-phenylpropyl, and the like), naphthylmethyl (e.g., 1-naphthylmethyl, 2-naphthylmethyl, and the like), and anthrylmethyl (e.g., 9-anthrylmethyl, and the like), and the like. Benzyl, and the like are preferable.
xe2x80x9cHeteroarylxe2x80x9d as used herein comprises a 5 to 6-membered aromatic ring including one or more atoms arbitrarily selected from oxygen atom, sulfur atom or nitrogen atom within the ring. Heteroaryl may be fused with cycloalkyl, aryl, or other heteroaryl at any possible position. Regardless whether the heteroaryl is monocyclic or fused cyclic, the heteroaryl can bind at any possible position.
Examples of the heteroaryl include pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), imidazolyl (e.g., 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g., 2-indolizinyl, 6-indolizinyl), isoindolyl (e.g., 2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), purinyl (e.g., 8-purinyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl, 5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g., 2-naphthyridinyl), quinolanyl (e.g.,2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g., 2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), and benzothienyl (e.g., 2-benzothienyl). As xe2x80x9cheteroarylxe2x80x9d of R1, imidazolyl and the like are preferable.
xe2x80x9cHeteroarylalkylxe2x80x9d as used herein comprises the above-described xe2x80x9clower alkylxe2x80x9d substituted with the above-described xe2x80x9cheteroarylxe2x80x9d, where such a substitution may be carried out at any possible position.
xe2x80x9cOptionally substituted lower alkylxe2x80x9d at R1 as used herein comprises the above-described xe2x80x9clower alkylxe2x80x9d which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituent include lower alkyloxy, halogen, and the like. Examples of the xe2x80x9coptionally substituted lower alkylxe2x80x9d include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and trifluoromethyl, and the like. An unsubstituted lower alkyl is preferable.
xe2x80x9cOptionally substituted alkylxe2x80x9d at Y as used herein comprises the above-described xe2x80x9calkylxe2x80x9d which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), carboxy, carbamoyl, alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SOpRA (p is an integer of 1 to 3, RA is hydrogen or alkyl), PO(OH)2 or P(O)OH which may be substituted with alkyl, substituted or unsubstituted amino (e.g., methyl amino, dimethyl amino, and carbamoyl amino), optionally substituted aryl (e.g., phenyl and tolyl), optionally substituted heteroaryl, optionally substituted nonaromatic heterocyclic group, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, nonaromatic heterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino, alkyloxyamino, formyl, and the like. Examples of the xe2x80x9coptionally substituted alkylxe2x80x9d include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl, piperidinomethyl, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, and morpholinocarbonylmethyl, acetyloxymethyl, and the like. An unsubstituted alkyl is preferable, particularly methyl.
xe2x80x9cOptionally substituted arylxe2x80x9d as used herein comprises the above-described xe2x80x9carylxe2x80x9d which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituent include lower alkyloxy and halogen, and the like. Examples of the xe2x80x9coption ally substituted arylxe2x80x9d include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and the like. An unsubstituted aryl is preferable.
xe2x80x9cOptionally substituted heteroarylxe2x80x9d as used herein comprises the above-described xe2x80x9cheteroarylxe2x80x9d which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituents include lower alkyloxy, halogen, and the like. Examples of the xe2x80x9coptionally substituted heteroarylxe2x80x9d include 2-chloroimidazole-5-yl, 4-chloroimidazole-5-yl, and the like. An unsubstituted heteroaryl is preferable.
xe2x80x9cOptionally substituted aralkylxe2x80x9d as used herein comprises the above-described xe2x80x9caralkylxe2x80x9d which may have one or more substituents at any possible positions, such as hydroxy, alkyloxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e. g. , methylthio) , cycloalkyl (e. g. , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen (e.g., fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, and the like. Preferable examples of the substituents include lower alkyloxy, halogen, and the like. Examples of the xe2x80x9coptionally substituted aralkylxe2x80x9d include furyl, thienyl, pyridyl, 5-chlorofuryl, 5-thienyl, 3-chloropyridyl, and the like. An unsubstituted aralkyl is preferable.
The product ion method of the present invention will be described in detail in which a starting material is one optically active substance. When the other material is used, similar reactions can be carried out. When a starting material has a substituent which is an obstacle to a reaction in first to sixth steps shown below, the starting material may be protected in advance in accordance with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons), and the like, and deprotected in an appropriate stage. 
wherein R1, R2, R3, and Y are as described above.
(First Step)
In the first step, R2OC(xe2x95x90O)-Hal, wherein Hal is halogen, [R2OC(xe2x95x90O)]2O, and the like are caused to react with a compound represented by a general formula (V-A) to obtain a compound (VII-A) in which an amino group is protected by R2OC(xe2x95x90O)xe2x80x94. This step can be carried out in accordance with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons), and the like.
For example, a compound represented by a general formula (V-A) is caused to react with 1.0 equivalent to 3.0 equivalents, preferably 1.0 equivalent to 1.5 equivalents, of R2OC(xe2x95x90O)-Hal, wherein Hal is halogen, and 2.0 equivalents to 6.0 equivalents, preferably 2.0 equivalents to 3.0 equivalents, of an organic base (e.g., triethylamine, and the like) or an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like), in a mixed solvent, such as water-toluene, water-dioxane, water-acetone, and the like, or a solvent, such as water, dioxane, and the like at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 0.5 to 3 hours to obtain a compound represented by a general formula (VII-A).
In the above-described IV), xe2x80x9cstep of protecting an amino group with R2OC(xe2x95x90O)xe2x80x94xe2x80x9d refers to this first step.
(Second Step)
In the second step, the carboxyl group of a compound represented by a general formula (VII-A) is esterified to obtain a compound represented by a general formula (II-A). This step can be carried out by a commonly used esterification.
For example, a compound represented by the general formula (VII-A) is dissolved in a solvent, such as methanol, ethanol, isopropyl alcohol, and the like, and allowed to react with 1 equivalent to 5 equivalents, preferably 1 equivalent to 2 equivalents, of a halogenating agent, such as thionyl chloride, hydrochloric acid, phosphorus oxychloride, and the like, at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 25xc2x0 C., one hour to 24 hours, preferably one hour to 3 hours to obtain a compound represented by a general formula (II-A).
In the above-described IV), xe2x80x9cstep of esterifying a carboxyl groupxe2x80x9d refers to this second step.
(Third Step)
The third step is a cyclization reaction in which the stereochemistry of R1 is reversed.
For example, a compound represented by a general formula (I-A) can be obtained in accordance with 1) to 3) described below. 1) a compound represented by a general formula (II-A) is dissolved in a solvent, such as toluene, ethyl acetate, cyclohexane, acetonitrile, and the like, preferably toluene. The amount of the solvent is preferably 1 V to 50 V, particularly 1 V to 10 V, where use of 1 ml of a solvent with respect to 1 g of a starting material is referred to as 1 V. 2) 1.0 equivalent to 20 equivalents, preferably 1.0 equivalent to 2.0 equivalents, of thionyl chloride are added at 25xc2x0 C. to 80xc2x0 C., preferably 25xc2x0 C. to 50xc2x0 C. Thionyl chloride can be used as a solvent. 3) The reaction solution is stirred at 25xc2x0 C. to 80xc2x0 C., preferably 60xc2x0 C. to 80xc2x0 C., for 5 hours to 48 hours, preferably 6 hours to 12 hours.
In this reaction, the closer the equivalent value of thionyl chloride is to 1.0 and the higher the xe2x80x9cVxe2x80x9d value of the amount of the solvent, the proportion of the cis-form of the intended compound was increased (the proportion of the trans-form was decreased).
The yield of the total compound s of cis-form and trans-form is not substantially affected by the equivalent value of thionyl chloride and the amount of the solvent.
In the above-described IV), xe2x80x9cstep of treating with thionyl chloridexe2x80x9d refers to this third step.
(Fourth Step)
In the fourth step, an ester compound represented by the general formula (I-A) is hydrolyzed to carboxylic acid. This step can be carried out by a commonly used hydrolysis.
For example, a compound represented by the general formula (I-A) is dissolved in a solvent, such as water, and the like, and 0.1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, of acid (e.g., hydrochloric acid, sulfuric acid, and the like) are added to the solution at 0xc2x0 C. to 100xc2x0 C., preferably 25xc2x0 C. to 80xc2x0 C. The resultant solution is allowed to react at 25xc2x0 C. to 100xc2x0 C., preferably 50xc2x0 C. to 80xc2x0 C. for 1 hour to 5 hours to obtain a compound represented by a general formula (III-A). This step can be carried out under basic conditions.
(Fifth Step)
In the fifth step, a compound represented by the general formula (III-A) is hydrolyzed to obtain allo-amino acid derivatives represented by a general formula (IV-A).
For example, a compound represented by the general formula (III-A) is dissolved in a solvent, such as water, and 0.1 equivalent to 20 equivalents, preferably 1 equivalent to 10 equivalents, of acid (e.g., hydrochloric acid, sulfuric acid, and the like) are added to the solution at 0xc2x0 C. to 100xc2x0 C., preferably 25xc2x0 C. to 80xc2x0 C. The resultant solution is allowed to react at 25xc2x0 C. to 100xc2x0 C., preferably 80xc2x0 C. to 100xc2x0 C. for 1 hour to 48 hours to obtain a compound represented by the general formula (IV-A).
(Sixth Step) (Peptide Bond Formation)
Three amino acid derivatives are subjected to two peptide bond formation to synthesize a compound (VI) (WO98/08867). A compound represented by the general formula (I-A) obtained by the above-described method is used to synthesize the compound (VI) in the following two methods (method A and method B). 
wherein R4 is the protecting group of a carboxyl group, R5 is the protecting group of an amino group, and R1 and Y are as described above.
Method Axe2x80x94First Step
The carboxyl group of 3-(4-thiazole)alanine synthesized in accordance with a method described in Synth. Commun., 20, 22, 3507 (1990) and Chem. Pharm. Bull., 38, 1, 103 (1990), is protected as an ester, such as methyl ester, benzyl ester, t-butyl ester, diphenylmethyl ester, and the like, resulting in a compound represented by a general formula (VIII). This compound and a compound represented by the general formula (III-A) are subjected to a peptide bond formation.
When the carboxyl group is protected as diphenylmethyl ester, the protecting reaction can be carried out as follows. 3-(4-thiazole)alanine is dissolved in a mixed solvent of an alcohol solvent, such as methanol, ethanol, and the like and a solvent, such as tetrahydrofuran, dioxane, and the like. 1 to 3 equivalents, preferably 1 to 2 equivalents, of diphenyl diazomethane are added to the solution at 0 to 50xc2x0 C., preferably 20 to 40xc2x0 C. for 10 minutes to 1 hour, preferably 20 to 40 minutes. The resultant solution is allowed to react at the same temperature for 30 minutes to 3 hours, preferably 1 to 2 hours while being stirred.
The peptide bond formation is described in xe2x80x9cPeputido Gosei [Peptide Synthesis]xe2x80x9d (Nobuo Izumiya, Maruzen), and the like, and can be carried out by such a commonly used peptide bond formation method.
As commonly used peptide bond formation methods, a method employing a condensing agent, such as N,N-dicyclohexylcarbodiimide (DCC), and the like, an azide method, an acid chloride method, an acid anhydride method, an active ester method, and the like. When a starting material has a substituent (amino, carboxy, hydroxyl, and the like) which is an obstacle to the peptide formation, the substituent can be protected in advance in accordance with a method described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons), and the like, and the protecting group is removed at a desired stage.
A compound represented by the general formula (VIII) and a compound represented by the general formula (III-A) are dissolved in a solvent, such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and the like. An N,N-dimethylformamide solution of a base, such as triethylamine, and the like, and dicyclohexylcarbodiimide (DCC), is added to that solution at xe2x88x9210 to 10xc2x0 C., preferably in ice bath. 1-hydroxybenzotriazole may be added. The resultant solution is stirred at 10 to 50xc2x0 C., preferably 20 to 30xc2x0 C., for one hour to one day, preferably 5 to 10 hours, followed by typical subsequent processes. Thus, a compound represented by a general formula (IX) can be obtained.
Method Axe2x80x94Second Step
A deprotecting reaction can be carried out by a commonly used deprotecting reaction (Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley and Sons)). For example, when R4 is diphenylmethyl, a compound represented by a general formula (IX) can be added to anisole and trifluoro aceticacidat xe2x88x9210 to 10xc2x0 C., preferably in ice bath. The mixture is stirred at the same temperature for 5 to 30 minutes, preferably 10 to 20 minutes. After the mixture is warmed to 20 to 40xc2x0 C., the mixture can be stirred for 1 to 4 hours, preferably 2 to 3 hours.
The resultant deprotected substance can be reacted with a pyrrolidine derivative synthesized by a method described in Tetrahedron, 27, 2599 (1971) through a peptide bond formation similar to method Axe2x80x94first step, thereby obtaining a compound represented by the general formula (VI).
Method Bxe2x80x94First Step
The amino group of 3-(4-thiazole)alanine synthesized in accordance with a method described in Synth. Commun., 20, 22, 3507 (1990) and Chem. Pharm. Bull., 38, 1, 103 (1990), is protected by a protecting group for an amino group, such as t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl, trifluoroacetyl, and the like to obtain a compound represented by a general formula (X). This compound and a pyrrolidine derivative synthesized by a method described in Tetrahedron, 27, 2599 (1971) are subjected to a peptide bond formation.
When t-butyloxycarbonyl is used for the protection, the protecting reaction can be carried out as follows. 3-(4-thiazole)alanine is dissolved in a solvent, such as dioxane, tetrahydrofuran, acetonitrile, and the like. Boc2O is added to the solution at 0 to 50xc2x0 C., preferably 10 to 30xc2x0 C., and stirred for 1 to 5 hours, preferably 2 to 4 hours.
A peptide bond formation can be carried out in a manner similar to that of the above-described method Axe2x80x94First step.
Method Bxe2x80x94Second Step
A deprotecting reaction for an amino group can be carried out as follows. When the protecting group is t-butyloxycarbonyl, a compound represented by a general formula (XI) is dissolved in a solvent, such as ethyl acetate, and the like. 1 to 4 N hydrochloric acid-ethyl acetate solution is added to that solution at xe2x88x9210 to 30xc2x0 C., preferably in ice. The resultant mixture is stirred at the same temperature for 1 to 5 hours, preferably 2 to 3 hours.
The resultant deprotected substance can be subjected to a peptide bond formation similar to that of method Axe2x80x94First step, thereby obtaining a compound represented by the general formula (VI).
In the production method, a compound represented by the general formula (V-A) or (V-B) is preferably L-threonine or D-threonine (R1=methyl). Further, compounds represented by the general formulas (VII-A), (VII-B), (II-A), (II-B), (I-A), (I-B), (III-A), (III-B), (IV-A), (IV-B), and (VI) are also preferably compounds derived from L-threonine or D-threonine.
As R2, benzyl is preferable. As R3 and Y, methyl is preferable.